Swyer syndrome (XY Gonadal dysgenesis) - DHH, MAP3K1, NR5A1 and SRY genes

Swyer's syndrome, also known as XY gonadal dysgenesis, is an alteration that affects sexual development and is characterized by a lack of correlation between the manifested sexual phenotype -female- and the genotype - XY, male-. At birth, patients present a normal female phenotype, but at puberty, they usually do not develop, or do so late, secondary sexual characteristics, have amenorrhea and have an increased risk of suffering a gonadal tumor. Swyer's syndrome usually only affects sexual development, and in this case patients are considered as isolated Swyer's syndrome. However, depending on the genetic cause, Swyer syndrome may be accompanied by other health disorders such as neuropathy or as part of a syndrome such as campomelic dysplasia, which causes serious skeletal abnormalities.

In some cases, Swyer's syndrome is due to mutations in the DHH or MAP3K1 genes (18% of cases), NR5A1 or SRY genes (15% of cases). Other cases are due to certain non-genetic factors, such as hormonal medications administered during pregnancy. However, in most people with Swyer's syndrome, the cause is unknown.

The DHH gene, located on the long arm of chromosome 12 (12q13.1), encodes a member of the "hedgehog" family of proteins. It is believed that this protein is involved in male sexual development and in the formation of the perineurium. Mutations of the DHH gene have been identified in a small number of people with Swyer's syndrome. These genetic changes affect the process of sexual differentiation, inhibiting the development of the male gonads and giving rise to the development of female reproductive structures (a uterus and fallopian tubes).

Mutations in the MAP3K1 gene, located on the long arm of chromosome 5 (5q11.2) represent approximately 18% of the cases of Swyer's syndrome. This gene encodes a protein that helps regulate the signaling pathways that control various processes in the body, including the processes of determining sexual characteristics before birth. MAP3K1 protein aggregates bind to other molecules called cofactors (RHOA, MAP3K4, FRAT1, and AXIN1), to help control the activity of signaling pathways. Mutations in the MAP3K1 gene increase cofactor binding, which decreases signaling that leads to male sexual differentiation and improves signaling that leads to female sexual differentiation. As a consequence, affected individuals do not develop male gonads (testes) and develop female reproductive structures.

On the other hand, mutations in the NR5A1 gene, located on the long arm of chromosome 9 (9q33), have been identified in a small number of people with Swyer's syndrome. This gene encodes a transcription factor called steroidogenic factor 1, which helps control the activity of several genes related to the development of the gonads and the adrenal glands. Therefore, mutations in this gene affect the process of sexual differentiation, causing female reproductive structures to develop instead of male gonads.

Finally, the SRY gene, located in the distal region of the short arm of the Y chromosome (Yp11.3), encodes a transcription factor of 204 amino acids member of the high mobility group (HMG: High Movility Group), which is involved in the mediation of protein binding to DNA, suggesting some regulatory function. In fact, it is believed that it can exert the function of a modular architecture factor of local chromatin, so that it is responsible for the assembly of the transcriptional machinery, regulating the expression of genes involved in sexual differentiation. Therefore, to a large extent, this protein was compared with the TDF, being, therefore, responsible for the start in the determination of the male sex by activating the gene responsible for the Mullerian inhibitory substance (MIS). In XY individuals, the mutations that take place in the SRY gene can alter the DNA binding of this transcription factor and, with it, its regulatory function on the transcriptional machinery. In this way, female phenotypes can be generated as a consequence of the failure in the differentiation of the gonads. In 15-30% of patients with complete XY gonadal dysgenesis, abnormalities in the SRY gene have been detected. So far, more than 60 mutations have been reported in this gene, especially in the HMG domain. The majority of mutations are specific to each individual.

Most cases of Swyer's syndrome are not inherited and occur in people with no history of the disease in their family. These cases are due to non-genetic causes or new mutations in a gene that occur during the formation of reproductive cells or early embryonic development. The Swyer´s syndrome related to SRY gene is usually due to a new mutation. However, some individuals inherit an altered SRY gene from an unaffected parent that has the mutation in some cells, but not in others. In rare cases, a parent can carry the mutation in every cell of the organism, but it also has other genetic variations that prevent the disease from expressing itself. When the disease is associated with mutations in the MAP3K1 or NR5A1 gene, the disease is also usually due to a new mutation. In rare hereditary cases, the mutation can be inherited from either of the parents, since these genes are not found on the Y chromosome. In these cases, it is considered to have an autosomal dominant inheritance pattern, which means that a copy of the altered gene in each cell is sufficient to express the disease. On the other hand, when the Swyer´s syndrome is due to mutations in the DHH gene, it is inherited with an autosomal recessive pattern, which means that both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition are carriers of a copy of the altered gene. Women who carry a mutation of the DHH gene generally have normal sexual development. Males carrying a mutation of the DHH gene may also have normal sexual development, or may have genital differences, such as hypospadias. 

Tests performed in IVAMI: in IVAMI we perform the detection of mutations associated with gonadal dysgenesis, by means of the complete PCR amplification of the exons of the DHH, MAP3K1, NR5A1 and/or SRY genes, respectively, and their subsequent sequencing.

Recommended samples: non-coagulated blood obtained with EDTA for separation of blood leucocytes, or a card with a dried blood sample (IVAMI can mail the card to deposit the blood sample).